This is a five-year application to support the full-time pursuit of the candidate's current research focus: understanding the molecular basis of head and neck cancer development. The candidate is currently an assistant professor of oral and maxillofacial surgery at the Harvard School of Dental Medicine. The candidate's research effort has been supported previously by an Institutional Dental Scientist Award (K16) and a Small Grant (R03), and is currently being conducted under a FIRST Award, all from the National Institute of Dental and Craniofacial Research. Funding from the proposed application will enable the candidate to pursue immediate and long-term career objectives in his overall goal toward establishing a productive career in academic dental medicine. The candidate's immediate career objectives are to pursue full-time research to test the hypothesis that tumor necrosis factor-alpha (TNF- alpha) mediated doc-1 gene expression is a critical event lost during head and neck cancer development. Preliminary studies in the candidate's research project demonstrate TNF-alpha dramatically up-regulates doc-1 expression in malignant oral keratinocytes and ectopic expression of doc- 1 markedly elevates the fraction of cells undergoing apoptosis Therefore, studies are proposed to define the mechanism of TNF-alpha mediated doc-1 expression, verify induction of apoptosis in human malignant oral keratinocytes and explore doc-1 as a therapeutic target in human oral squamous cell carcinomas. Verification of the role of the TNF-alpha/doc- 1 pathway in apoptosis and its use as a gene therapeutic target are directions that have evolved from the candidate's FIRST Award research plan and may serve as a basis for a future R01 application. The candidate's long-term objective is to establish a productive career in academic dental medicine with a special emphasis on translating basic research in tumor biology, such as TNF-alpha/doc-1 pathway and apoptosis, towards desperately needed improvement in head and neck cancer patient care. To ensure the candidate will become an important integral part of its research and academic program, the Harvard School of Dental Medicine is uniquely qualified to support his research career development plan through a strong institutional commitment to the candidate and access to senior collaborators throughout the Harvard Medical Teaching Campus who have a similar objective: to develop a biologically-based approach to advance cancer diagnosis and treatment.